This invention relates to vitamin D compounds and their pharmaceutical uses. In particular, the invention relates to 1α,25-dihydroxy-24,24-difluoro-2-methylene-19-nor-vitamin D analogs and their pharmaceutical uses.
The biologically active metabolite of vitamin D3, 1α,25-(OH)2D3 (i.e., the native hormone or “calcitriol”) is best known for its regulation of calcium and phosphorus homeostasis, but it also plays a role in controlling other biological functions such as induction of cell differentiation or proliferation. The use of calcitriol in hyperproliferative disorders is limited by its calcemic effects, and therefore there is a continuing interest in chemically modified analogues of 1α,25-(OH)2D3 and their clinical applications.1 
The native hormone undergoes chemical transformations in vivo, such as 23S- and 24R-hydroxylation catalyzed by CYP24A1 hydroxylase, oxidation of the 24-hydroxy group to a ketone, and cleavage of the C-23-C-24 bond of (23S)-23,25-dihydroxy-24-oxovitamin D3.2 By preventing or slowing this catabolic degradation, for instance by introducing fluorine atoms, analogues with a longer life-time that are more resistant to oxidation can be prepared.3 The substitution of hydrogen atoms with fluorine atoms is dictated by physical and chemical properties. The high electronegativity of fluorine, its small size, the good overlap of the 2s or 2p orbitals with corresponding orbitals of carbon as well as the presence of three lone pairs of electrons mean that C—F bonds are always polarized from the sp3 carbon atom (δ+) to the fluorine atom (δ−). Because of the C—F bond's stability and the similar size of hydrogen and fluorine atoms, fluorinated vitamin D analogues have been prepared which exhibit slower catabolism degradation.4,5 
Fluorine-substituted side-chain analogues were synthesized first in the early 1980s. The use of 24,24-difluoro-25-hydroxyvitamin D3 was used to show that 24-hydroxylation is not required for the action of vitamin D.6 Falecalcitriol (26,27-hexafluorocalcitriol) marketed for the treatment of hypocalcemia, rickets, and osteomalacia was found to be several times more potent then calcitriol both in vitro and in vivo systems, with a longer duration of its action in vivo.7 Numerous other modifications on the fluorinated side chain (e.g., a double8-10 and a triple9 bonds, sulfone,8 a carbonyl group,10 oxetan11) as well as introduction of a fluorine atom on the A ring of vitamin D3 have also been investigated.12 
In addition to fluorination, the stereochemistry of vitamin D analogues also has been shown to affect biological activity. For example, the native hormone has (20R) stereochemistry, and it has been found that a 20-epimer analogue of 1α,25-(OH)2D3 having (20S) stereochemistry rather than (20R) stereochemistry exhibits increased biological activities. Furthermore, the position of the methylene group on the A ring of vitamin D analogues has been shown to affect biological activity. For example, the native hormone has a C-10 methylene group, and the combination of C-20 epimerization from 20R stereochemistry to 20S stereochemistry and replacement of the methylene group from the C-10 carbon to the C-2 carbon results in an analogue that exhibits increased bone synthesis activity and increased resorption activity (i.e., increased turnover activity).
Here, we now have found replacement of the C-10 methylene group to the C-2 carbon (i.e., “2-methylene substitution”) markedly increases bone calcium mobilizing activity when the configuration of C-20 is in the R configuration in 24,24-difluoro-19-nor-1α,25-dihydroxyvitamin D compounds. However, when the C-20 is in the S configuration in 24,24-difluoro-19-nor-1α,25-dihydroxyvitamin D compounds, 2-methylene substitution has little or no effect on bone calcium mobilization activity.